Substituted nicotinamides and analogs as activators of caspases and inducers of apoptosis and the use thereof

Abstract

The present invention is directed to substituted nicotinamides and analogs thereof, represented by Formula V:or a pharmaceutically acceptable salt or prodrug thereof, wherein:Ar' and Ar are independently optionally substituted aryl or optionally substituted heteroaryl, provided that the ring structure of said optionally substituted heteroaryl comprises not more than two nitrogen atoms; andR11 is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted.The present invention also relates to the discovery that compounds having Formula V are activators of caspases and inducers of apoptosis. Therefore, the compounds of this invention may be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.

What is claimed is:  
     
       1. A compound of Formula III:                    
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
       R 1  and R 5  are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, halogen, NO 2 , cyano, haloalkyl, haloalkoxy, amino and aminoalkyl, provided that at least one of R 1  and R 5  is selected from the group consisting of NO 2 , cyano, alkyl and haloalkyl;  
       R 2  and R 4  are independently selected from the group consisting of hydrogen, hydroxy, halogen, cyano, haloalkyl, haloalkoxy, amino and aminoalkyl;  
       R 3  is propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, octyl, Cl, F, haloalkyl, alkoxy, arylalkoxy, cyano, haloalkyloxy, amino or aniinoalkyl;  
       R 6  is hydrogen, hydroxy, alkyl, NO 2 , cyano, haloalkyl, haloalkyloxy, amino or aminoalkyl;  
       R 7  is hydrogen, hydroxy, alkyl, NO 2 , cyano, haloalkyl, haloalkyloxy, amino or aminoalkyl;  
       R 9  is hydroxy, alkyl, halogen, NO 2 , haloalkyl, alkoxy, cyano, haloalkyloxy, amino or aminoalkyl;  
       R 10  is hydrogen, hydroxy, alkyl, Cl, F, NO 2 , cyano, haloalkyl, haloalkyloxy, amino or aminoalkyl; and  
       R 11  is hydrogen, alkyl or haloalkyl;  
       wherein said prodrug is:  
       a) an ester of a carboxylic acid containing compound of Formula III obtained by condensation with a C 1-4  alcohol;  
       b) an ester of a hydroxyl group containing compound of Formula III obtained by condensation with a C 1-4  carboxylic acid, C 3-6  dioic acid or anhydride thereof;  
       c) an imine of an amine group containing compound of Formula III obtained by condensation with a C 1-4  aldehyde or ketone; or  
       d) an acetal or ketal of at least one of the R 1-10  hydroxy containing groups obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether.  
     
     
       2. The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
       6-Chloro-N-(4,5-difluoro-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(3-bromo-4-methoxy-6-nitrophenyl)-3-pyridinecarboxamide;  
       5,6-Dichloro-N-(4-methoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(2-methyl-4-methoxyphenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-ethoxy-2-nitrophenyl)-N-methyl-3-pyridinecarboxamide;  
       6-Chloro-N-(2-cyano-4,5-dimethoxyphenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-chloro-2-trifluoromethylphenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-chloro-2-cyanophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(2,4-dimethyl-6-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(3,4-dimethoxy-6-nitrophenyl)-3-pyridinecarboxamide; and  
       6-Chloro-N-(2-cyano-4-methylphenyl)-3-pyridinecarboxamide.  
     
     
       3. The compound of  claim 1 , wherein said compound is of Formula IV:                    
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
       4. The compound of  claim 3 , wherein said compound is selected from the group consisting of: 
       6-Chloro-N-(4-methoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-methoxy-2-nitrophenyl)-1-N-oxide-3-pyridinecarboxamide;  
       6-Chloro-N-(4-chloro-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Fluoro-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-trifluoromethyl-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(2-nitro-4-trifluoromethoxy]phenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-benzyloxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Methyl-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-cyano-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-(2,2,2-Trifluoroethoxy)-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Dimethylamino-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-t-butyl-2-nitrophenyl)-3-pyridinecarboxamide; and  
       6-Trifluoromethyl-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide.  
     
     
       5. A compound selected from the group consisting of 6-Chloro-N-(2,4-dimethyl-6-nitrophenyl)-3-pyridinecarboxamide, 6-Chloro-N-(4-methyl-2-nitrophenyl)-3-pyridinecarboxamide, and 4-Chloromethyl-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide. 
     
     
       6. A pharmaceutical composition, comprising the compound of any one of claims  1 - 4 , and a pharmaceutically acceptable carrier. 
     
     
       7. A method of treating a disorder responsive to the induction of apoptosis in an animal suffering therefrom, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula                    
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
       R 7  and R 9 -R 10  are independently hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, a heterocyclic group, fused heterocyclic, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, beteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, aryloxy, arylalkoxy, carbonylainido, alkyithiol, —NH 2 , —NHR 15  or —NR 15 R 16 ;  
       R 1  is halo, aryl, fused aryl, carbocyclic, fused carbocyclic, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkyithiol, —NH 2 , —NHR 15 , or —NR 15 R 16 ;  
       R 2 -R 5  are hydrogen, halo, aryl, fused aryl, carbocyclic, fused carbocyclic, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalicyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkyithiol, —NH 2 , —NHR 15  or —NR 15 R 16 ;  
       R 6  is hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, a heterocyclic group, fused heterocyclic, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkyithiol, —NH 2 , —NHR 15  or —NR 15 R 16 , wherein  
       R 15  and R 16  are independently optionally substituted C 1-10  alkyl, heterocyclic or heteroaryl groups; and  
       R 11  is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted;  
       wherein said disorder responsive to the induction of apoptosis is a cancer selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lyruphocytic leukemia, carcinoma, cervical carcinoma chronic granulocytic leukemia, acute granulocytic leukemia, and hairy cell leukemia; and  
       wherein said prodrug is:  
       a) an ester of a carboxylic acid containing compound of Formula III obtained by condensation with a C 1-4  alcohol;  
       b) an ester of a hydroxyl group containing compound of Formula III obtained by condensation with a C 1-4  carboxylic acid, C 3-6  dioic acid or anhydride thereof;  
       c) an imine of an amine group containing compound of Formula III obtained by condensation with a C 1-4  aldehyde or ketone; or  
       d) an acetal or ketal of at least one of the R 1-10  hydroxy containing groups obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether.  
     
     
       8. The method of  claim 7 , wherein R 1  and R 2 , or R 2  and R 3 , or R 3  and R 4 , or R 4  and R 5  are taken together to form an optionally substituted carbocycle. 
     
     
       9. The method of  claim 8 , wherein R 1  and R 2 , or R 2  and R 3 , or R 3  and R 4 , or R 4  and R 5  are taken together to form —(CH 2 ) 3 —, —(CH 2 ) 4 —, or —CH═CH—CH═CH—, wherein the carbocycle is optionally substituted. 
     
     
       10. The method of  claim 7 , wherein R 6 , R 7  and R 10  are independently hydrogen or fluoro. 
     
     
       11. The method of  claim 7 , wherein R 1  is nitro. 
     
     
       12. The method of  claim 7 , wherein R 2 , R 4 , and R 5  are independently hydrogen or fluoro. 
     
     
       13. The method of  claim 7 , wherein said compound is selected from the group consisting of: 
       N-(4-Methyl-2-nitrophenyl)-3-pyridinecarboxamide;  
       N-(4-Ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       N-(4-Methoxy-2-nitrophenyl)-3-pyridinecarboxanlide;  
       6-Chloro-N-(4,5-difluoro-2-nitrophenyl)-3-pyridinecarboxaniide;  
       6-Chloro-N-(3-bromo-4-methoxy-6-nitrophenyl)-3-pyridinecarboxamide;  
       5,6-Dichloro-N-(4-methoxy-2-nitrophenyl)-3-pyridinecarboxaniide;  
       6-Chloro-N-(2-methyl-4-methoxyphenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-ethoxy-2-nitrophenyl)-N-methyl-3-pyridinecarboxamide;  
       6-Chloro-N-(2-cyao-4,5-dimethoxyphenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-chloro-2-cyanophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(2,4-dimethyl-6-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(3,4-dimethoxy-6-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(2-cyano-4-methylphenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-chloro-2-methyl-6-nitrophenyl)-3-pyridinecarboxamide, and  
       4-Trifluoromethyl-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide.  
     
     
       14. The method of  claim 7 , wherein said compound is of Formula IV:                    
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
       15. The method of  claim 14 , wherein said compound is selected from the group consisting of: 
       6-Chloro-N-(4-methoxy-2-nitrophenyl)-3-pyridinecarboXafllide;  
       6-Chloro-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxanlide;  
       6-Chloro-N-(4-methyl-2-nitrophenyl)-3-pyridinecarboxainide;  
       6-Chloro-N-(4-mcthoxy-2-nitrophenyl)-1-N-oxide-3-pyridinecarboxamide;  
       6-Chloro-N-(4-chloro-2-nitrophenyl)-3-pyridinecarboxaflhide;  
       6-Fluoro-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarbOxaflhide;  
       6-Chloro-N-(4-fluoro-2-nitrophenyl)-3-pyridinecarboxaflhide;  
       6-Chloro-N-(4-benzyloxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Methyl-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxaniide;  
       6-Chloro-N-(4-cyano-2-nitropbenyl)-3-pyridinecarboxaniide;  
       6-(2,2,2-Trifluoroethoxy)-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Dimethylamino-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Chloro-N-(4-t-butyl-2-nitrophenyl)-3-pyridinecarboxamide;  
       6-Trifluoromethyl-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide; and  
       6-Chloromethyl-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxaniide.  
     
     
       16. A method for treating cancer, comprising administering to an animal in need of such treatment an effective amount of a compound of Formula m:                    
       or a pharmaceutically acceptable salt or prodrug thereof, wherein 
       R 7  and R 9 -R 10  are independently hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, a heterocyclic group, fused heterocyclic, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkylthiol, —NH 2 , —NHR 15  or —NR 15 R 16 ;  
       R 1 -R 5  are hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylailcynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkyithiol, —NH 2 , —NHR 15  or —NR 15 R 16 ;  
       R 6  is hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, a heterocyclic group, fused heterocyclic, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkyithiol, —NH 2 , —NHR 15  or —NR 15 R 16 , wherein  
       R 15  and R 16  are independently optionally substituted C 1-10  alkyl, heterocyclic or heteroaryl groups; and  
       R 11  is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted;  
       wherein said cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, breast carcinoma, cervical carcinoma, chronic granulocytic leukemia, acute granulocytic leukemia, and hairy cell leukemia; and  
       wherein said prodrug is:  
       a) an ester of a carboxylic acid containing compound of Formula III obtained by condensation with a C 1-4  alcohol;  
       b) an ester of a hydroxyl group containing compound of Formula III obtained by condensation with a C 1-4  carboxylic acid, C 3-6  dioic acid or anhydride thereof;  
       c) an imine of an amine group containing compound of Formula III obtained by condensation with a C 1-4  aldehyde or ketone; or  
       d) an acetal or ketal of at least one of the R 1-10  hydroxy containing groups obtained by condensation with chioromethyl methyl ether or chloromethyl ethyl ether.  
     
     
       17. The method of  claim 16 , wherein said compound is of Formula IV:                    
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
       18. A method for the treatment of drug resistant cancer, comprising administering to an animal in need of such treatment an effective amount of a compound of the Formula III:                    
       or a pharmaceutically acceptable salt or prodrug thereof, wherein: 
       R 7  and R 9 -R 10  are independently hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, a heterocyclic group, fused heterocyclic, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aniinoalkyl, cyano, cyanoalkyl, acyl, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkylthiol, —NH 2 , —NHR 15  or —NR 15 R 16 ;  
       R 1 -R 5  are hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylallcyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylaniido, hydroxy, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkyithiol, —NH 2 , —NHR 15  or —NR 15 R 16 ;  
       R 6  is hydrogen, halo, haloalkyl, haloalkoxy, aryl, fused aryl, carbocyclic, fused carbocyclic, a heterocyclic group, fused heterocyclic, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, nitro, aminoalkyl, cyano, cyanoalkyl, acyl, acylamido, thiol, acyloxy, azido, alkoxy, alkoxycarbonyl, aryloxy, arylalkoxy, carboxy, carbonylamido, alkyithiol, —NH 2 , —NHR 15  or —NR 15 R 16 , wherein  
       R 15  and R 16  are independently optionally substituted C 1-10  alkyl, heterocyclic or heteroaryl groups; and  
       R 11  is hydrogen; or alkyl, cycloalkyl, aryl or heteroaryl, each of which is optionally substituted;  
       wherein said cancer is selected from the group consisting of Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, breast carcinoma, cervical carcinoma, chronic granulocytic leukemia, acute granulocytic leukemia, and hairy cell leukemia; and  
       wherein said prodrug is:  
       a) an ester of a carboxylic acid containing compound of Formula III obtained by condensation with a C 1-4  alcohol;  
       b) an ester of a hydroxyl group containing compound of Formula III obtained by condensation with a C 1-4  carboxylic acid, C 3-6  dioic acid or anhydride thereof;  
       c) an imine of an amine group containing compound of Formula III obtained by condensation with a C 1-4  aldehyde or ketone; or  
       d) an acetal or ketal of at least one of the R 1-10  hydroxy containing groups obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether.  
     
     
       19. The method of any one of claims  7 ,  16 , and  18  wherein optional substituents on the alkyl or heteroaryl group of R 15  and R 16  or the alkyl, aryl, or heteroaryl group of R 11  include one or more halo, C 1 -C 6  haloalkyl, C 6 -C 10  aryl, C 4 -C 7  cycloalkyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6-C   10  aryl(C 1 -C 6 )alkyl, C 6 -C 10  aryl(C 2 -C 6 )alkenyl, C 6 -C 10  aryl(C 2 -C 6 )alkynyl, C 1 -C 6  hydroxyalkyl, nitro, amino, ureido, cyano, C 1 -C 6  acylamino, hydroxy, thiol, C 1 -C 6  acyloxy, azido, C 1 -C 6  alkoxy or carboxy. 
     
     
       20. The method of  claim 18 , wherein said compound is of Formula IV:                    
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
       21. The method of  claim 16  or  18 , additionally comprising treating said animal with radiation-therapy. 
     
     
       22. The method of  claim 16  or  18 , wherein said compound is administered after the surgical treatment of said animal for cancer. 
     
     
       23. The method of  claim 7 , wherein said disorder is breast carcinoma. 
     
     
       24. The method of  claim 7 , wherein said disorder is cervical carcinoma. 
     
     
       25. The method of  claim 7 , wherein said disorder is Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, chronic granulocytic leukemia, acute granulocytic leukemia, or hairy cell leukemia.